title: Systemic low-molecular weight drug delivery to pre-selected neuronal regions.
abstract: We describe a procedure for controlled, periodic, reversible modulation of selected regions of the blood-brain barrier (BBB) or the inner-blood-retina barrier (iBRB) based on incorporation into an AAV-2/9 vector of a doxycycline-inducible gene encoding shRNA targeting claudin-5, one of 30 or so proteins constituting the BBB and iBRB. The vector may be introduced stereotaxically into pre-selected regions of the brain or into the retina, rendering these regions permeable to low-molecular weight compounds up to approximately 1 kDa for the period of time during which the inducing agent, doxycycline, is administered in drinking water, but excluding potentially toxic higher molecular weight materials. We report on the use of barrier modulation in tandem with systemic drug therapy to prevent retinal degeneration and to suppress laser-induced choroidal neovascularization (CNV), the latter being the hallmark pathology associated with the exudative, or wet, form of age-related macular degeneration (AMD). These observations constitute the basis of a minimally invasive systemic therapeutic modality for retinal diseases, including retinitis pigmentosa and AMD, where, in early stage disease, the iBRB is intact and impervious to systemically administered drugs.
authors.affiliation: Ocular Genetics Unit, Department of Genetics, Trinity College Dublin, Dublin 2, Ireland. matthew.campbell@tcd.ie
authors.forename: Matthew
authors.initials: M
authors.lastname: Campbell
authors.forename: Marian M
authors.initials: MM
authors.lastname: Humphries
authors.forename: Anna-Sophia
authors.initials: AS
authors.lastname: Kiang
authors.forename: Anh T H
authors.initials: AT
authors.lastname: Nguyen
authors.forename: Oliviero L
authors.initials: OL
authors.lastname: Gobbo
authors.forename: Lawrence C S
authors.initials: LC
authors.lastname: Tam
authors.forename: Mayu
authors.initials: M
authors.lastname: Suzuki
authors.forename: Finnian
authors.initials: F
authors.lastname: Hanrahan
authors.forename: Ema
authors.initials: E
authors.lastname: Ozaki
authors.forename: G-Jane
authors.initials: GJ
authors.lastname: Farrar
authors.forename: Paul F
authors.initials: PF
authors.lastname: Kenna
authors.forename: Peter
authors.initials: P
authors.lastname: Humphries
mesh_terms: D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D002460:Cell Line; D062507:Claudin-5; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D062507:Claudin-5; C491511:Cldn5 protein, mouse; D008565:Membrane Proteins; D034741:RNA, Small Interfering